TY - JOUR
T1 - Dose–response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin
AU - Lorza, Andres M.Arias
AU - Ravi, Harshan
AU - Philip, Rohit C.
AU - Galons, Jean Philippe
AU - Trouard, Theodore P.
AU - Parra, Nestor A.
AU - Von Hoff, Daniel D.
AU - Read, William L.
AU - Tibes, Raoul
AU - Korn, Ronald L.
AU - Raghunand, Natarajan
N1 - Funding Information:
This study was supported by research funding from EpiCept Corporation and the National Institutes of Health (P30 CA076292, IRAT Core). The authors gratefully acknowledge the contributions of patients and their families to make this study possible.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2–3 days post-crolibulin (13–24 mg/m2). ADC maps were computed from DW-MRI. Pre-contrast T1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC90s) and the Extended Tofts Model parameters ktrans, ve, and vp were calculated. There was a strong correlation between higher plasma drug Cmax and a linear combination of (1) reduction in tumor fraction with AUC90s> 15.8 mM s, and, (2) increase in tumor fraction with ve< 0.3. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with ADC<1.1×10-3mm2/s, and, (2) increase in tumor fraction with ve< 0.3. These findings are suggestive of cell swelling and decreased tumor perfusion 2–3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.
AB - The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2–3 days post-crolibulin (13–24 mg/m2). ADC maps were computed from DW-MRI. Pre-contrast T1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC90s) and the Extended Tofts Model parameters ktrans, ve, and vp were calculated. There was a strong correlation between higher plasma drug Cmax and a linear combination of (1) reduction in tumor fraction with AUC90s> 15.8 mM s, and, (2) increase in tumor fraction with ve< 0.3. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with ADC<1.1×10-3mm2/s, and, (2) increase in tumor fraction with ve< 0.3. These findings are suggestive of cell swelling and decreased tumor perfusion 2–3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.
UR - http://www.scopus.com/inward/record.url?scp=85090081169&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85090081169&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-71246-w
DO - 10.1038/s41598-020-71246-w
M3 - Article
C2 - 32879326
AN - SCOPUS:85090081169
VL - 10
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 14449
ER -